Entospletinib alleviates acute liver injury and acute kidney injury by inhibiting ferroptosis

Ferroptosis, an iron-dependent form of regulated cell death characterised by lipid peroxidation, has been implicated in the pathogenesis of various diseases and conditions, including organ injury, neurodegeneration, cancer, and autoimmune disorders. Inhibition of ferroptosis using small-molecule compounds is considered a promising approach for treating ferroptosis-related diseases. In this study, we screened a small-molecule compound library and identified entospletinib (Ent) as a universal and highly effective ferroptosis inhibitor. Ent inhibited ferroptosis induced by various stimuli and protected various cell lines from ferroptosis. Mechanistically, Ent reduced lipid peroxidation and suppressed the expression of haeme oxygenase 1 induced by RSL3. Furthermore, Ent alleviated concanavalin A-induced acute liver injury and cisplatin-induced acute kidney injury in vivo. Our findings demonstrate that Ent is an effective ferroptosis inhibitor, both in vivo and in vitro, suggesting its potential therapeutic value in the treatment of ferroptosis-related diseases.